Abstract
A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b–c, and 7e–g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a–c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets.
Highlights
Cancer ranks second of the top ten mortal diseases around the world, especially in the industrialized countries, highlighting the imperative need to discover novel therapies and approaches to cure this disease [1,2]
This design strategy led to a set of novel compounds that might have cytotoxic effects via EGFR TK and tubulin inhibitory mechanisms and looks like the reference drugs
These results suggest that the molecular target of these chalcone derivatives might be tubulin, and their strong anti-tubulin polymerization activity corresponds well with their cytotoxicity
Summary
Cancer ranks second of the top ten mortal diseases around the world, especially in the industrialized countries, highlighting the imperative need to discover novel therapies and approaches to cure this disease [1,2]. The tubulin inhibitory potential of boronic acid chalcone analogs [45], cinnamic acyl sulfonamide derivatives [46] and chalcone-based azacarbolines [47] has been reported In view of these facts, we report a facile synthesis of new series of triazoloquinoxaline-chalcone derivatives as a privileged bioactive scaffold. The presence of the triazoloquinoxaline moiety linked to the aromatic chalcone scaffold moiety might provide a rigid arrangement of the two aryl rings that enhances their activity. This design strategy led to a set of novel compounds that might have cytotoxic effects via EGFR TK and tubulin inhibitory mechanisms and looks like the reference drugs
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